Process for preparing 3-chloro-5-nitrotoluene

Abstract

 A preparation process of 3-chloro-5-nitrotoluene is provided in mild conditions. It is a process for preparing 3-chloro-5-nitrotoluene, which comprises reacting 2-methyl-4-nitroaniline with achlorinating agent such as 5-butyl hypochlorite in a neutral condition to obtain 2-chloro-4-nitro-6-methylaniline and deaminating the 2-chloro-4-nitro-6-methylaniline to obtain 3-chloro-5-nitrotoluene.

Description

Field of arts of the invention

[0001] The invention relates to a process for preparing 3-chloro-5-nitrotoluene and a process for preparing 3-chloro-5-methylphenylisocyanate.

Prior arts

[0002] JP-A 8-231489 and J. Med. Chem. 43, 4726-4737 (2000) show a process for preparing an isocyanate reacting with a polysaccharide and having a high separation power.

[0003] JP-A 8-231489 discloses a production process using potassium chloride in hydrochloric acid. The reference production process needs any improvement because a strong acid is used and a salt formed by neutralization of the product mixture has to be treated.

[0004] J. Med. Chem. discloses a reaction of 4-methyl-2-nitroaniline with N-chlorosuccinic imide. In the reference reaction, purification with column chromatography is necessary to separate the intended product from a side-produced succinic imide. It is not suitable to a large-scaled production.

Summary of the invention

[0005] The invention relates to a process for preparing 3-chloro-5-nitrotoluene in mild conditions, without any strong acid and any strong base, to obtain an isocyanate precursor , and then a process for preparing 3-chloro-5-methylphenylisocyanate, which is useful to produce an optical separation agent.

[0006] The invention provides, as means to solve the above shown problems, a process for preparing 3-chloro-5-nitrotoluene, which comprises reacting 2-methyl-4-nitroaniline with a chlorinating agent in a neutral condition to obtain 2-chloro-4-nitro-6-methylaniline and deaminating the 2-chloro-4-nitro-6-methylaniline to obtain 3-chloro-5-nitrotoluene.

[0007] The invention provides, as means to solve another problem, a process for preparing 3-chloro-5-methylphenylisocyanate, which comprises reducing 3-chloro-5-nitrotoluene obtained by the above shown process and reacting the resulting product with triphosgene.

Detailed explanation of the invention

[0008] The preparation of 3-chloro-5-nitrotoluene will be explained in line with the following reaction formula 1.

[0009] 2-methyl-4-nitroaniline, (1) of the reaction formula 1, is first reacted with a chlorinating agent in a neutral condition to obtain 2-chloro-4-nitro-6-methylaniline, (2) of the reaction formula 1.

[0010] The reaction is preferably carried out in a solvent containing neither acid nor base at room temperature. The solvent is not particularly limited, as far as it is a solvent for both 2-methyl-4-nitroaniline and the chlorinating agent, including, for example, toluene, benzene, acetic acid etc.

[0011] The chlorinating agent includes, for example, t-butylhypochlorite, N-chlorosuccinic imide etc.

[0012] The reaction product of 2-chloro-4-nitro-6-methylaniline is isolatedby filtering etc. inadvance to the subsequent reaction step. It may be washed or dried if necessary.

[0013] Then 3-chloro-5-nitrotoluene, (3) of the reaction formula 1, is obtained from 2-chloro-4-nitro-6-methylaniline by deamination.

[0014] The deamination reaction for 2-chloro-4-nitro-6-methylaniline may proceed in a solvent such as ethanol or methanol. The reaction temperature is preferably controlled into plural steps in the following manner.

[0015] In the first step, the reaction mixture is adjusted between room temperature and 0°C, preferably 5 and 10°C, and then sodium nitrite is added thereto, preferably in the form of an aqueous solution of sodium nitrite of 1 to 2 mole equivalents.

[0016] In the second step, the reaction mixture is allowed to stand, preferably stirred, at room temperature, it is observed that the temperature elevates up to about 45°C by way of the reaction heat and then decreases down to lower than 40°C, then the reaction mixture is stirred at a temperature of 40 to 50°C until no foaming.

[0017] In the third step, the reaction mixture is cooled to room temperature and the reaction product is isolated by filtering or the like.

[0018] The preparation of 3-chloro-5-methylphenylisocyanate will be below explained in line with the following reaction formula 2.

[0019] 3-chloro-5-nitrotoluene, (3) of the reaction formula 2, is first dissolved in a solvent such as ethanol and the solution is reacted, while cooled, with a reducing agent (a hydrogenating agent) such as tin chloride or Raney nickel to obtain 3-chloro-5-methylaniline, (4) of reaction formula 2.

[0020] Triphosgene is dissolved in a solvent such as toluene and 3-chloro-5-methylaniline and a toluene solution of triethylamine are added thereto at room temperature for reaction to obtain 3-chloro-5-methylphenylisocyanate, (5) of reaction formula 2.

[0021] 3-chloro-5-nitrotoluene, obtained by the preparation of the invention, is useful as a precursor to 3-chloro-5-methylphenylisocyanate. 3-chloro-5-methylphenylisocyanate is useful to prepare conventional polysaccharides used as optical separating agents.

[0022] The process of the invention is carried out in mild conditions and suitable to a large scaled production.

Example

[0023] The invention will be below explained by reference to examples. The invention, however, is not limitedby the examples.

Example 1 (preparation of 3-chloro-5-nitrotoluene)

① preparation of 2-chloro-4-nitro-6-methylaniline

[0024] 2-methyl-4-nitroaniline (56.0g, 0.368mol) was dispersed in toluene (430ml) in a 1 liter four-neck flask. Tirtiary butyl hypochloride (46.0g, 0.423mol) was added dropwise thereto, while cooled in iced water and stirred. The mixture was stirred at room temperature for 3 hours. The solid was filtered and washed three times with 200 ml of a 50% aqueous ethanol three times. It was then dried at 40°C at a reduced pressure to obtain 55.33 g of a yellow solid (production yield 80%). The yellow solid was used at the subsequent step without purification.
¹H-NMR, 500MHz, in CDCl₃ (δ)
   8.12 (d, J = 2.2Hz, 1H)
   7.92 (d, J = 2.2Hz, 1H)
   4.73 (bs, 2H)
   2.27 (s, 3H)

② preparation of 3-chloro-5-nitrotoluene

[0025] 2-chloro-4-nitro-6-methylaniline (55.0g, 0.295mol) and ethanol (500ml) were mixed in a 2 litter four-neck flask. A conc. Sulfuric acid (120ml) was added dropwise to the reaction mixture at a temperature being lower than room temperature. The reaction mixture was maintained at a temperature of 5 to 10°C and an aqueous solution of sodium nitrite (26.44g, 0.381mol/40ml) was added dropwise thereto over a period of 40 minutes.

[0026] The reaction mixture was then stirred at room temperature. It was observed that the temperature elevated up to 45°C by way of the reaction heat and then decreases down to lower than 40°C and then the reaction mixture was stirred at a temperature of 40 to 45°C until no foaming.

[0027] The product mixture was cooled to room temperature and poured into 2500 ml of iced water to obtain precipitates. They were filtered and dried at a reduced pressure to obtain 45.95 g of a yellow solid (production yield 90%).
¹H-NMR, 500MHz, in CDCl₃ (δ)
   8.03 (bs, 1H)
   7.94 (bs, 1H)
   7.50 (bs, 1H)
   2.46 (s, 3H)

Example 2 (preparation of 3-chloro-5-methylphenylisocyanate)

① preparation of 3-chloro-5-methylaniline

[0028] 3-chloro-5-nitrotoluene (45g, 0.241mol) and ethanol (500ml) were mixed in a 2 litter four-neck flask. The mixture was cooled to about 4°C. A solution of tin chloride monohydrate (217.67g, 0.965mol) in 200ml of ethanol was added dropwise to the mixture over 2 hours, while the reaction mixture was maintained at 10°C or lower.

[0029] Then the reaction product mixture was stirred at room temperature for 2 hours and poured into 2500 ml of iced water. It was neutralized with sodium hydroxide and filtered with a nutsche filled with sellaite. The residue was washed with ethyl acetate. The intended product was obtained with ethyl acetate from the filtrate liquid.

[0030] Then the extract liquid and the washing liquid were jointed. The mixture was washed with water and then a saturated salt water and dried with magnesium sulfate. Concentrated, it was treated by distillation at a reduced pressure to obtain 28.0 g of a yellow liquid (production yield 80%).
   B.p. : 85-92°C/0.4kPa or lower (3Torr or lower)
   ¹H-NMR, 500MHz, in CDCl₃ (δ)
   6.56 (bs, 1H)
   6.48 (dd, JI, J2=1.3Hz, 1H)
   6.36 (bs, 1H)
   3.64 (bs, 2H)
   2.22 (s, 3H)

② preparation of 3-chloro-5-methylphenylisocyanate

[0031] Triphosgene (17.01g, 0.0573mol) was dissolved in 200ml of tolunen in a 1 liter flask. 150 ml of a toluene solution of 3-chloro-5-methylaniline (21.9g, 0.155mol) and triethylamine (36.0ml) was added dropwise thereto over 30 minutes at room temperature.

[0032] The reaction mixture was then stirred at 70°C for 2 hours and cooled to room temperature. The obtained precipitates of hydrochloric acid salt of triethylamine were filtered out and the filtrate liquid was concentrated and treated with distillation at a reduced pressure to obtain 16.87 g of a colorless liquid (production yield 65%).
   B.p.: 72-74°C/0.53-0.66kPa (4-5Torr)
   ¹H-NMR, 500MHz, in CDCl₃ (δ)
   7.00 (bs, 1H)
   6.90 (bs, 1H)
   6.80 (bs, 1H)
   2.31 (s, 3H)

Claims

1. A process for preparing 3-chloro-5-nitrotoluene, which comprises reacting 2-methyl-4-nitroaniline with a chlorinating agent in a neutral condition to obtain 2-chloro-4-nitro-6-methylaniline and deaminating the 2-chloro-4-nitro-6-methylaniline to obtain 3-chloro-5-nitrotoluene.

2. The process as claimed in Claim 1, in which the reaction of 2-methyl-4-nitroaniline with a chlorinating agent is carried out in a solvent containing neither acid nor base.

3. The process as claimed in Claim 1 or 2, in which the chlorinating agent is t-butylhypochlorite.

4. The process as claimed in any of Claims 1 to 3, in which the deamination is carried out by adding sodium nitrite to the reactant mixture adjusted between room temperature and 0°C, allowing the reaction mixture to stand at an elevated temperature and then decreasing the temperature and keeping it at a temperature of 40 to 50°C.

5. A process for preparing 3-chloro-5-methylphenylisocyanate, which comprises reducing 3-chloro-5-nitrotoluene obtained by any process as defined in Claims 1 to 4 and reacting the resulting product with triphosgene.